Phosphate tightly associated with a molecule, e.g., a protein, has been known since the late nineteenth century. Since then, a variety of covalent linkages of phosphate to proteins have been found. The most common involve esterification of phosphate to serine, threonine, and tyrosine with smaller amounts being linked to lysine, arginine, histidine, aspartic acid, glutamic acid, and cysteine. The occurrence of phosphorylated molecules, e.g., proteins, implies the existence of one or more kinases, e.g., protein kinases, capable of phosphorylating various molecules, e.g., amino acid residues on proteins, and also of phosphatases, e.g., protein phosphatases, capable of hydrolyzing various phosphorylated molecules, e.g., phosphorylated amino acid residues on proteins.
Protein kinases play critical roles in the regulation of biochemical and morphological changes associated with cellular growth and division (D'Urso et al. (1990) Science 250:786–791; Birchmeier et al. (1993) Bioessays 15:185–189). They serve as growth factor receptors and signal transducers and have been implicated in cellular transformation and malignancy (Hunter et al. (1992) Cell 70:375–387; Posada et al. (1992) Mol. Biol. Cell 3:583–592; Hunter et al. (1994) Cell 79:573–582). For example, protein kinases have been shown to participate in the transmission of signals from growth-factor receptors (Sturgill et al. (1988) Nature 344:715–718; Gomez et al. (1991) Nature 353:170–173), control of entry of cells into mitosis (Nurse (1990) Nature 344:503–508; Maller (1991) Curr. Opin. Cell Biol. 3:269–275) and regulation of actin bundling (Husain-Chishti et al. (1988) Nature 334:718–721).
Protein kinases can be divided into different groups based on either amino acid sequence similarity or specificity for either serine/threonine or tyrosine residues. A small number of dual-specificity kinases have also been described. Within the broad classification, kinases can be further subdivided into families whose members share a higher degree of catalytic domain amino acid sequence identity and also have similar biochemical properties. Most protein kinase family members also share structural features outside the kinase domain that reflect their particular cellular roles. These include regulatory domains that control kinase activity or interaction with other proteins (Hanks et al. (1988) Science 241:42–52).
The entry and progression of cells through the cell cycle are controlled by changes in the levels and activities of cyclins. The levels of several of the cyclins (A, B, and E) peak during specific phases of the cell cycle, then are rapidly degraded as the cell enters the next phase of the cell cycle. Cyclins perform their function by forming complexes with a group of constitutively expressed proteins called cyclin-depended kinases (CDKs). Different combinations of cyclins and CDKs are associated with each of the important transitions in the cell cycle.
Cyclin B is synthesized and binds to CDK1 during the transition of the cell into the G2 phase of the cell cycle. This forms the B/CDK1 complex which is necessary for the cells to enter the M phase. The complex is activated by phosphorylation, and the active kinase then phosphorylates a variety of proteins involved in mitosis, DNA replication, depolymerization of the nuclear lamina, and mitotic spindle formation.
Kinases play a role in the transduction of signals for cell proliferation, differentiation, and apoptosis. Alteration in such genes and their products are frequent in human cancers. Deregulated cell proliferation is the hallmark of cancer. Alteration in such genes and their products are frequent in human cancer. Modulation of these genes and their regulatory activities may permit the control of tumor cell proliferation and invasion.
Kinases play critical roles in cellular growth. Therefore, novel kinase polynucleotides and proteins are useful for modulating cellular growth, differentiation and/or development.